Alkyl substituted 2-thiohydantoins as anti-convulsants



3,013,943 ALKYL SUBSTITUTED Z-THIGHYDANTOINS AS ANTI-CGNVULSANTS Arthur Berger, Sirokie, Ills, assignor to Baxter Lahoratories, Ina, Morton Grove, III., a. corporation of Delaware No Drawing. Filed Apr. It 1959, Ser. No. 805,636 Claims. (Cl. 167-45) This invention relates to new therapeutic compositions and, more particularly, to therapeutic compositions which are especially useful in preventing convulsive seizures such as those associated with epilepsy.

This application is a continuation-in-part of my copending application, Serial No. 707,479, filed January 7, 1958, now abandoned.

There are three distinct types of epileptic seizuresgrand mal, petit mal, and. psychornotor seizures. A patient may be subject to only one of these types, or he may be subject to any combination of them. Because of the complexity of the disease, there has not yet been found one single drug which is universally effective. The clinical efiicacy of the anti-epileptic drugs varies in different patients; one agent or combination may sueceed where others have failed. For many patients, the so-called refractory patients, there is no effective therapy. As a consequence, the search continues for new drugs or combinations of drugs which can be added to the physicians armamentarium.

In accordance with this invention, epilepsy is treated by administering anti-epileptic preparations which here tofore have had no therapeutic or pharmaceutical applications. These preparations are highly effective at substantially smaller dosage levels than are necessarily employed with the presently available commercial antiepileptic preparations. Because of their efficacy at loW dosage levels, the compositions of this invention show distinct promise in a field of medicine where presently employed agents have quite generally been characterized by a number of undesirable side effects such as sedation, dizziness and other toxicmanifestations.

The compositions of this invention which are especially useful in combatting convulsive seizures contain a pharmaceutical carrier and a compound having the following structural formula:

| H1 7 NR4 in which R is an alkyl radical having from 1 to 7 carbon atoms and R is an allyl radical or a lower alkyl radical having from 1 to 4 carbon atoms. In the preferred compositions of this invention, R is an alkyl radical having from 2 to 4 carbon atoms and R is an allyl radical or a lower alkyl radical having from 1 to 4 carbon atoms.

The following compounds are representative of those which are useful in the practice of .this invention: 3-allyl- 5 isobutyl 2 thiohydantoin, 3 ethyl 5 isobutyl- 2-thiohydantoin, 3-ethyl-5-sec.butyl-Z-thiohydantoin, 3- ethyl 5 isopro-pyl 2 thiohydantoin, 3,5 diisobutyl- 2 thiohydantoin, 3 methyl 5 isobutyl 2 thio hydantoin, and 3-allyl-5-heptyl-2-thiohydantoin.

While numerous hydantoins have been screened for anti-convulsant activity, and have been shown to have such activity in greater or lesser degree, their corresponding Z-thio derivatives have shown little or no activity. In contrast, the Z-thiohydantoins employed in the practice of this invention, especially those specifically mentioned above, show unexpectedly superior activity as anti- States Patent convulsants, while the corresponding hydantoin derivatives are essentially inactive.

Certain of the Z-thiohydantoins of this invention are known chemical compounds. One such compound, 3- allyl-S-isobutyl-2-thiohydantoin, is disclosed by Seiichi Oba, Yasuo Kaseka and. Kihachi Fukawa, in J. Soc. Sci., Phot. Japan, 13, No. 3, 25 (1951), abstracted in Chemical Abstracts 46, 2938 (1952). These Z-thiohydantoins have never been shown to have any pharmaceutical applications.

The compositions of this invention may take the form of tablets, powders, capsules or other dosage forms. The compositions employed in the methods'of this invention may take, the form of active anti-convulsant material admixed with solid diluents and/or tableted adjuvants such as cornstarch, lactose, talc, stearic acid, magnesium stearate, gums or the like. Any of the tableting materials used in pharmaceutical practice may be employed where there is no incompatibility with the active anti-convulsant material. The material may be tableted with or without: adjuvants. Alternatively, the anti-convulsant material with its adjuvant material may be placed in the usual capsule or resorbable material, such as the usual gelatin capsule, and administered in that form.

A more comprehensive understanding of this invention is obtained by reference to the following examples.

EXAMPLE I A graphic illustration of the superiority of the 2- thiohydantoins of this invention is shown by the data set forth in Table 1 below. These data compare the anti-epileptic efficacy of the compositions of this inven-' tion with that of commercially available anti-convulsant agents which are commonly employed in the treatment of epilepsy. In the tests reported in Table l, laboratory animals were subjected to established and conventional convulsion-inducing procedures. These procedures are known as: (l) Electroshock and (2) Metrazol-induced shock. In the electroshock procedure, electrical current of the order of 40'milliamperes is sent through the animal (mouse) for about 0.2 second, the time of appli cation of the electroshock coinciding with the peak ef fect of the medicament which is being given to the animal. In the Metrazol test, about 1.4-1.7 milligrams of Metrazol is administered to the animal, this being the normal lethal dose. The Metrazol is administered at the time of the peak effect of the medicament, as in the case of electroshock. Activity against electroshock is usually correlated with clinical efiicacy against grand mal epileptic seizures. Activity against Metrazol-induced shock is usually correlated with clinical eflicacy against petit mal epileptic seizures.

Presented in Table 1 are the results of tests in which the following compositions of this invention were employed: 3-allyl-5-isobutyl-2-thiohydantoin, 3-ethyl-5-isobutyl-Z-thiohydantoin, 3-ethyl-S-sec.butyl-Z-thiohydantoin, and 3-methyl-5-isobutyI-Z-thiohydantoin. Also included are certain commercial anti-convulsants which enjoy wide-spread therapeutic usage. The commercial anti-epileptic agents which are employed for comparison purposes are sodium 5,5-diphenylhydantoin (commercially available as a trademarked composition Dilantin), phenacetylcarbamide (commercially available as Phenurone), and 3,5,5-trimethyloxazolidines2,4-dione (commercially available as Tridione).

One of the test parameters employed is the E3 expressed in milligrams of medicament employed per kilogram of body weight of the test animal. The ED of a particular compound is' that quantity of compound which, when introduced into the test animals, will pro- 3 tect 50% of the animals from the eifeets of the electroshock or Metrazol-induced shock. In arriving at the ED ten or more animals are employed for each composition which is tested. For animal testing work, the active ingredient is extended by suspending it in a suspension of gum acacia in normal saline.

Another test parameter reported in Table 1 is the protective index which is expressed in terms of the TD ED The TD is the amount of anti-convulsant material per kilogram of body weight of the test animal, which will induce a toxic reaction in 50% of a group of ten or more test animals. The protective index is a measure of neurological deficit, i.e., the extent to which toxic symptoms can be anticipated in the use of a particular material. The higher the protective index, the less likely is the incidence of toxic reactions. The protective index is provided only for that test procedure which demonstrates the principal activity for the anti-convulsant material being tested, i.e., electroshock or Metrazol. For example, the ED for 3-allyl-5-isobutyl-2-thiohydantoin is much lower in the Metrazol test than in the electroshock test. The protective index of this compound, therefore, is provided only for the Metrazol activity.

The data in the foregoing table show that the 2- thiohydantoins of the invention are much more efiicacious when used at small dosage levels for the treatment of induced seizures, particularly seizures of the Metrazol type, than are the presently available commercial anticonvulsant preparations. This is of considerable importance since all of the known anti-convulsants caused numerous undesirable side effects when used in the high dosage quantity which is generally required to achieve the desired anti-convulsant eifect.

Since the compositions of this invention have high protective indices and may be used at low dosage levels, side effects which are a toxic manifestation, are minimized. As has been indicated hereinbefore, the pharmacological screening method which employs Metrazolinduced shock is usually correlated with anti-convulsant activity of the petit mal epileptic type seizures. The data in Table 1 show that the compositions of this invention have pronounced activity in protecting against Metrazolinduced seizures. Since these compositions also have relatively high protective indices, they are particularly promising as therapeutic agents of value in the treatment and prevention of petit mal seizures.

A satisfactory adult human dosage will range from about to about 10,000 milligrams per day of the efiective ingredient which is contained in the compositions of this invention.

The foregoing detailed description has been given for clearness of understanding only, and no unnecessary limitations are to be inferred therefrom.

What is claimed is:

1. In a method of preventing convulsive seizures in human beings who are subject to such seizures, the step of administering to such human beings from about 100 to about 10,000 milligrams per day of a thiohydantoin of the following composition:

RCH-CO HN NR1 wherein R is a member selected from the group consisting of alkyl radicals having from 1 to 7 carbon atoms and R is a member selected from the group consisting of an allyl radical and an alkyl radical having from 1 to 4 carbon atoms.

2. The method of claim 1 in which the said thiohydantoin is 3-allyl-5-isobutyl-2-thiohydantoin.

3. The method of claim 1 in which the said thiohydantoin is 3-ethyl-5-isbutyl-2-thiohydantoin.

4. The method of claim 1 in which the said thiohydantoin is 3-ethyl-5-sec.butyl-2-tl1iohydantoin.

5. The method of claim 1 in which the said thiohydantoin is 3-methyl-5-isobutyl-2-thiohydantoin.

References Cited in the file of this patent C.A., v01. 50, 1956, pp. 943ld, 1731f (POSL). C.A., vol. 48, 1954, p. 7463g (POSL). C.A., vol. 46, 1952, p. 13138 (POSL). C.A., vol, 47, 1953, p. 9923g (POSL). 

1. IN A METHOD OF PREVENTING CONVULSIVE SEIZURES IN HUMAN BEINGS WHO ARE SUBJECT TO SUCH SEIZURES, THE STEP OF ADMINISTERING TO SUCH HUMAN BEINGS FROM ABOUT 100 TO ABOUT 10,000 MILLIGRAMS PER DAY OF A THIOHYDANTOIN OF THE FOLLOWING COMPOSITION: 